Cancer is an uncontrolled growth and spread of cells that may affect almost any tissue of the body. There are over 100 different types of cancer, and each is classified by the type of cell that is initially affected. The approach to the discovery of new anticancer drugs has recently evolved from a reliance on empiric cell-based screening for anti-proliferative effects to a more mechanistically based approach that targets the specific molecular lesions thought to be responsible for the development and maintenance of the malignant phenotype in various forms of cancer. Through this approach, the kinase inhibitors have emerged as a new class of anticancer drugs that are capable of directly interacting with the catalytic site of the target enzyme and thereby inhibiting kinase function or blocking kinase signaling. In 1994, Parke-Davis scientists reported the first generation of very potent kinase inhibitor with manifold selectivity against other kinases (Fry, D. V. et al., Science 1994, 265, 1093). This discovery spurred the development of projects throughout the pharmaceutical industry; and as of now 18 kinase inhibitors have been approved by FDA for various diseases, and more than 500 candidates are in active clinical development.
Phosphoinositide 3-kinases (PI3Ks) constitute a family of lipid kinases involved in the regulation of a network of signal transduction pathways that control a range of cellular processes (Ihle, N. T. and Powis, P. Mol. Cancer Ther. 2009, 8, 1; Vivanco, I. and Sawyers, C. L. Nature Rev. Cancer 2002, 2, 489). The PI3K signaling plays a central role in cellular processes critical for cancer progression, metabolism, growth, survival and motility. The PI3K family of enzymes is comprised of 15 lipid kinases with distinct substrate specificities, expression patterns, and modes of regulation. In particular, PI3K-α has emerged as an attractive target for cancer therapeutics. Significant efforts have been made to discover inhibitors of the PI3K pathway to treat cancers and several candidates have advanced to clinical studies such as XL-765 and XL-147 (Exelixis), which are class I PI3K inhibitors that have entered Phase I clinical studies for advanced solid tumors. Other PI3K inhibitors in clinical studies include BEZ-235 and BKM-120 (Phase II, Novartis) and GSK-1059615 (Phase I, GSK) for advanced solid tumors. AstraZeneca's AZD-6482, which is a PI3K-β inhibitor, has completed Phase I trials for the treatment of thrombosis. A quinazolinone-based isoform-specific PI3K-δ inhibitor CAL-101 (GS-1101, Gilead Sciences) is in Phase III and IC-87114 (Calistoga) has entered Phase I clinical trial. Other PI3K inhibitors in clinical trials include D106669 and D87503 (Phase I, Aeterna Zentaris), GDC-0941 (Phase I, Genentech) and PKI-587 (Phase I, Pfizer). In addition, several other PI3K inhibitors are in early stages of clinical trials.
Despite of the fact that large number of kinase inhibitors have received FDA-approval, the target selectivity remains a formidable challenge in drug development because almost all approved kinase inhibitor drugs works by competing with ATP for the ATP binding site of the enzyme. Hence, there is a great need for next-generation kinase inhibitors that work through alternative mechanisms such as allosteric inhibition. While recently approved kinase inhibitor drugs offer benefits for cancer treatment, further advances are required to effect tumor selective cell killing, avoid off-target related toxicities and improve survival rates (Bharate, S. B. et al., Chem. Rev. 2013, 113, 6761). Amongst the four isoforms of phosphoinositide 3-kinases, particularly the α-isoform has been found to be activated by mutation in several cancers; and therefore discovery of α-isoform selective inhibitor is highly important. BEZ-235 (Novartis molecule) is a pan-PI3K inhibitor inhibiting all four isoforms with IC50 values of 4, 76, 7 and 5 nM respectively; thus showing very poor selectivity towards α-isoform compared with β, γ and δ isoforms (19, 17.5 and 1.25 fold selectivity).